New Targets for A1C and Blood Pressure Control:

One Size Does Not Fit All

Ann Bullock, MD Division of Diabetes Treatment and Prevention

Indian Health Service

This presentation:

Give an overview of the evolution in the evidence for glucose and blood pressure targets in type 2 diabetes

Current status of glucose and blood pressure targets: one size doesn’t fit all

Clinical practice guidelines vs. performance measures What all this means for clinical practice

Remember when we thought that the same diabetes targets applied

to everyone? A1C <7% BP <130/80 mmHg LDL <100mg/dL

That is so 2007! Universal targets sure are easier for data people But they don’t work well for many of our patients “First, do no harm”

Glucose targets across the lifespan

“To everything ther e is a season…”

United Kingdom Prospective Diabetes Study (UKPDS)

Years

A1C (%)

6

7

8

9

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Conventional Group

Intensive Group

UKPDS Group Lancet 1998;352:837–53

UKPDS: Post-Trial Changes in A1C

UKPDS results presented

Mean (95%CI)

Holman RR, et al. New England Journal of Medicine 2008; 359:1577-1589

After median 8.8 years post-trial follow-up Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040

Microvascular disease RRR: 25% 24% P: 0.009 0.001

Myocardial infarction RRR: 16% 15% P: 0.052 0.014

All-cause mortality RRR: 6% 13% P: 0.44 0.007

UKPDS: “Legacy Effect” of Glucose Therapy

RRR = Relative Risk Reduction P = Log Rank

Holman et al. New England Journal of Medicine 2008; 359:1577-1589

The Legacy Effect: conclusions

“The UKPDS showed the benefits of an intensive strategy to control blood glucose levels in patients with type 2 diabetes sustained up to 10 yrs after cessation of the randomized intervention. Benefits persisted despite the early loss of within-trial differences in A1C levels between the intensive-therapy group and conventional-therapy group – a so-called legacy effect.”

Holman, et al. NEJM 2008. 359: 1577-1589

UKPDS Showed that glycemic control early in

diabetes has lasting benefit, including for CVD risk

However, it was interpreted as implying that everyone should have an A1C <7%--and national guidelines followed suit But UKPDS included only healthy,

newly-diagnosed patients <65 yrs old Lancet 1998;352:837-853

And then came major studies on intensive glucose control in more “real world” diabetes

populations

ACCORD, ADVANCE, and VADT NEJM 2008;358:245-259 and 2560-72, NEJM 2009;360:129-139

Showed little benefit to intensive glucose control other than for nephropathy (in ACCORD and ADVANCE)

And showed increased mortality (ACCORD), weight gain, and hypoglycemia

Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials

Study Microvasc CVD Mortality

UKPDS DCCT / EDIC*

ACCORD ADVANCE

VADT

Long Term Follow-up

Initial Trial

* in T1DM

Kendall DM, Bergenstal RM. © International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024)

2009 ADA Statement on Glucose Control and CVD Prevention

May not affect CVD outcomes after macrovascular disease established—but good glucose control in the early years of DM may affect long-term risk of macrovascular disease

Makes a difference in microvascular disease However, BG goal should be adjusted to the individual patient

In general, A1C goal: <7% Lower goal if short duration DM, long life expectancy,

and little co-morbidity Higher goal if the converse—there are risks with

aggressive control Intensive Glycemic Control and the Prevention of Cardiovascular Events:

Implications of the ACCORD, ADVANCE, and VA Diabetes Trials --A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association, January 2009

And the discussion has continued Meta-analysis of 13 recent RCTs (>34,000 pts) that evaluated

intensive glucose lowering: Limited benefits on all-cause and CV mortality At best, modest benefits for microvascular disease

↓ albuminuria, a trend toward ↓retinopathy, but little else Severe hypoglycemic events doubled BMJ 2011;343:d4243 doi:10.1136/bmj.d4243

Guidelines starting to reflect recent evidence, now Performance Measures are being re-thought Much more benefit to ↓ patient’s A1C from 9% to 7.1% than to ↓ it

from 7.1% to 6.9% Unknown effects of adding on multiple meds to achieve target Diabetes Care 2011;34:1651-1659

Management of Hyperglycemia in Type 2 Diabetes:

A Patient-Centered Approach

Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

3. ANTI-HYPERGLYCEMIC THERAPY • Glycemic targets

- HbA1c < 7.0% (mean PG ∼150-160 mg/dl [8.3-8.9 mmol/l])

- Pre-prandial PG <130 mg/dl (7.2 mmol/l)

- Post-prandial PG <180 mg/dl (10.0 mmol/l)

- Individualization is key:

Tighter targets (6.0 - 6.5%) - younger, healthier Looser targets (7.5 - 8.0%+) - older, comorbidities,

hypoglycemia prone, etc.

- Avoidance of hypoglycemia PG = plasma glucose

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

VA uses A1C target ranges Major comorbidity or physiologic age

Microvascular complications

Absent or mild Moderate Advanced Absent > 10 years of life expectancy < 7 < 8 8-9

Present 5-10 years of life expectancy < 8 < 8 8-9

Marked < 5 years of life expectancy

8-9 8-9 8-9

A1C Target Recommendations, VA/DoD Diabetes Practice Guidelines, 2010

American Geriatrics Society Five Things Physicians and Patients Should Question

#3: Avoid using medications to achieve hemoglobin A1c <7.5% in most adults age 65 and older; moderate control is generally better.

There is no evidence that using medications to achieve tight glycemic control in older adults with type 2 diabetes is beneficial. Among non-older adults, except for long-term reductions in myocardial infarction and mortality with metformin, using medications to achieve glycated hemoglobin levels less than 7% is associated with harms, including higher mortality rates. Tight control has been consistently shown to produce higher rates of hypoglycemia in older adults. Given the long timeframe to achieve theorized microvascular benefits of tight control, glycemic targets should reflect patient goals, health status, and life expectancy. Reasonable glycemic targets would be 7.0 – 7.5% in healthy older adults with long life expectancy, 7.5 – 8.0% in those with moderate comorbidity and a life expectancy < 10 years, and 8.0 – 9.0% in those with multiple morbidities and shorter life expectancy. “Choosing Wisely”, ABIM Foundation, 2013

“Wait a minute—what happened to all the hype about getting everyone’s A1C

down to <7% or even lower??”

bit of medication, do better in the long-run? Yes! But this is a marker of their overall systemic health

That is not the same thing as having to use 3 or 4 meds to beat someone’s glucoses down to achieve a low target Not known if polypharmacy is safe, effective or cost-effective Hypoglycemia risk increases

Performance measures (like GPRA) have reflected the national guidelines —and providers felt pressured to get all their patients’ A1Cs down to <7%, no matter what it took GPRA has already changed for 2013!

Do people who have A1Cs<7%, on their own or with a little

So, what do we do with all this? Individualize glucose targets—really!

Younger, healthier patients: aim for <7% (or lower) Excellent glucose control achieved and maintained early in the

course of diabetes has long-term benefits, including for CVD

Longer duration of diabetes, more co-morbidities and lots of meds already: liberalize glucose targets (ranges) Think carefully about whether to add another medication (and

which one) to lower glucose Hypoglycemia causes “considerable morbidity and even

mortality” Diabetes Care 2013;36:1384-1395

Focus some efforts on patients whose A1Cs >9.5% Future EHRs: help with selecting, documenting target for

each patient—VA already has a prototype

Absolute number of events prevented by different interventions per 1000 patient years of treatment (data taken from Cholesterol Treatment Trialists’ Collaboration and Blood Pressure

Lowering Treatment Trialists’ Collaboration).

Preiss D , Ray K K BMJ 2011;343:bmj.d4243

©2011 by British Medical Journal Publishing Group

Blood Pressure

A Similar Story

Blood Pressure Target As with glucose targets, UKPDS played a major

role in target selection for BP in international guidelines

For diastolic BP target, so did the randomized Hypertension Optimal Treatment (HOT) study Study paper noted ↓ CV risk in diabetic patients with

DBP <80 mm Hg Accompanying editorial noted slight ↑ mortality in

intensively treated diabetic patients with ischemic heart disease so recommended caution in lowering BP to <140/85 in this group Lancet 1998;351:1755-62 and 1748-1749

UKPDS • “This paper reports that patients with hypertension and type 2

diabetes assigned to tight control of blood pressure achieved a significant reduction in risk of 24% for any end points related to diabetes, 32% for death related to diabetes, 44% for stroke, and 37% for microvascular disease. In addition there was a 56% reduction in risk of heart failure. The mean blood pressure over nine years was 144/82mm Hg on tight control compared with a less tight control mean of 154/87mm Hg”

BMJ 1998;317(7160):703-713

• UKPDS observational study showed that “risk of diabetic complications was strongly associated with raised blood pressure. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure less than 120 mm Hg.”

BMJ 2000;321(7258):412-419

Blood Pressure Target: JNC 7

2003: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) Cited studies including UKPDS, HOT Agreed with ADA in recommending that pts with

DM have a BP goal ≤130/80 But noted that “available data are somewhat sparse

to justify the low target level of 130/80” Hypertension 2003;42:1206-52

Original Article “Effects of Intensive Blood-Pressure Control in

Type 2 Diabetes Mellitus”

Study Overview

•In a randomized trial, 4733 patients with type 2 diabetes mellitus who were at high risk for cardiovascular events received treatment aimed at a target systolic blood pressure of less than 120 mm Hg or less than 140 mm Hg •At a mean follow-up of 4.7 years, the rates of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) were not significantly different between the two trial groups

The ACCORD Study Group

N Engl J Med Volume 362(17):1575-1585

April 29, 2010

ACCORD

• “In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events.”

• “Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2372 participants in the standard-therapy group (1/3%) (P<0.001).”

• Accompanying editorial: “…now we learn from the completed ACCORD study that flexible goals should probably be applied to the control of hyperglycemia, blood pressure, and dyslipidemia in patients with type 2 diabetes, taking into account individual clinical factors of importance.”

NEJM 2010;362:1628-1629

International Verapamil SR-Trandolapril Study (INVEST)

Observational subgroup analysis of 6400 participants: ≥50 yrs old w/DM and CAD Tight control: able to maintain SBP <130 mm Hg Usual control: 130 to <140 Uncontrolled: ≥140

Conclusion: “Tight control of systolic BP among patients with diabetes and CAD was not associated with improved cardiovascular outcomes compared with usual control.”

JAMA 2010;304:61-68

Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial

(ONTARGET) 25,584 pts (9,603 diabetic) >55 yrs old w/↑ CVD risk

Randomized to ramipril +/- telmasartan Observed for 4.6 yrs Primary outcome: composite of CV death, nonfatal MI or stroke, hospitalized

heart failure

The higher the initial SBP, the more benefit to lowering BP For initial SBPs 130-142, benefit of lowering is primarily for stroke Initial SBP around or <130 , anti hypertensive treatment should be

implemented with caution because of possible cardiac effects J Am Coll Cardiol 2012;59:74-83

“Our study provides evidence that in high-CV-risk patients a BP reduction to <140/90 mm Hg is associated with CV protection. Overall CV protection, however, may not be improved by lower BP targets, as recommended for higher-risk subjects in current guidelines.”

Circulation 2011;124:1727-1736

HTN and Progression of CKD to End Stage Renal Disease (ESRD) Associations of SBP and DBP with risk of

progressing to ESRD in the Kidney Early Evaluation Program (KEEP) Large, diverse community-based sample

High SBP accounted for most of the risk for progression to ESRD Highest risk in those with SBP ≥150 mm Hg Risk started at SBP of 140 rather than at 130 Arch Intern Med 2012;172:41-47

Current BP Targets in Diabetes Numerous studies since ACCORD have shown that

risk for CVD, CKD starts at SBP of 140 mmHg (not 130 mmHg)

ADA 2013 Diabetes Care 2013;36(S1), pg. S29

“People with diabetes and hypertension should be treated to a systolic blood pressure goal of <140 mmHg.” “Lower systolic targets, such as <130 mmHg, may be appropriate

for certain individuals, such as younger patients, if it can be achieved without undue treatment burden.”

“Patients with diabetes should be treated to a DBP <80 mm Hg.”

VA/DoD Goal in their 2010 Guidelines: <140/80

Going Forward JNC 8 will hopefully weigh in on BP targets in Diabetes

DBP <80 or <90? Higher SBP target in elderly? Any change in order of use of BP med classes?

Target selection should be individualized <140 will work well for most patients

Good BP control definitely reduces CVD, CKD risks

Balance need for good BP control with risk of problems Hypotension, fatigue, polypharmacy issues are common Use caution in setting even <140 target in patients who have

symptoms at that SBP and/or with meds needed to achieve it Higher risk: Older, comorbidities, longer duration of DM, on lots of

meds, autonomic neuropathy

Clinical Practice Guidelines and Performance Measures

Clinical practice guidelines help clinicians take care of individual patients; have implications for population health e.g. ADA, IHS Diabetes Standards of Care

Performance measures evaluate the care given to groups/populations of patients—used for accountability e.g. GPRA

For years, clinical guidelines and GPRA targets for A1C and BP have been the same #’s (A1C <7%, BP <130/80) Was thought that “one size fit all” Has led to confusion about difference between clinical &

performance targets

So what about IHS GPRA 2013? How to pick a performance measure when patients should

have different targets? Target should cover most patients and minimize overtreatment/harm The need to individualize highlights difference between them

A1C Target: Individualize 6-8.5+% vs GPRA <8% BP Target: Individualize <140+/80-90+ vs GPRA <140/90

GPRA performance measures are not clinical practice guidelines Need to do what’s right for each patient

Some patients would benefit from lower A1C targets And both these GPRA targets will still be too stringent for our

older patients and those with multiple comorbidities

Diabetes Audit 2013

Audit New CVD question Removed ECG question

Audit reports Removed adjectives (“ideal”, “good”) for A1C, BP eGFR instead of creatinine Targeted CVD risk factor reduction

Antiplatelet agent, statin

Thank You!

Questions, comments?

IHS Divison of Diabetes website: www.diabetes.ihs.gov

ann.bullock@ihs.gov